Nomograms to predict long‐term survival for patients with gallbladder carcinoma after resection

Abstract Background Surgical resection remains the primary treatment option for gallbladder carcinoma (GBC). However, there is a pressing demand for prognostic tools that can refine patients' treatment choices and tailor personalized therapies accordingly. Aims The nomograms were constructed using the data of a training cohort (n = 378) of GBC patients at Eastern Hepatobiliary Surgery Hospital (EHBH) between 2008 and 2018. The model's performance was validated in GBC patients (n = 108) at Guangzhou Centre from 2007 to 2018. Methods and results The 5‐year overall survival (OS) rate in the training cohort was 24.4%. Multivariate analyses were performed using preoperative and postoperative data to identify independent predictors of OS. These predictors were then incorporated into preoperative and postoperative nomograms, respectively. The C‐index of the preoperative nomogram was 0.661 (95% CI, 0.627 to 0.694) for OS prediction and correctly delineated four subgroups (5‐year OS rates: 48.1%, 19.0%, 15.6%, and 8.1%, p < 0.001). The C‐index of the postoperative nomogram was 0.778 (95%CI, 0.756 –0.800). Furthermore, this nomogram was superior to the 8th TNM system in both C‐index and the net benefit on decision curve analysis. The results were externally validated. Conclusion The two nomograms showed an optimally prognostic prediction in GBC patients after curative‐intent resection.

precise prediction model for overall survival (OS) could prove instrumental in identifying high-risk subgroups with more unfavorable prognoses, enabling targeted treatment strategies post-resection.
The commonly employed staging system for gallbladder carcinoma (GBC) is the American Joint Committee on Cancer (AJCC) 8th staging system. 4This system is instrumental in customizing (neo)adjuvant therapies, predicting postsurgical prognosis, and guiding additional adjuvant treatment.However, the simplification process during the creation of this system could have led to the exclusion of several pivotal prognostic factors, including resection margin, tumor differentiation, and perineural invasion. 5As a result, the potential for effective prognostic stratification in the context of GBC remains subject to debate.
7][8] In fact, nomograms possess the unique capability to generate personalized predictions, making them an appealing substitute or alternative standard to the AJCC staging system. 9A notable example is the study conducted by Wang et al, which crafted a predictive nomogram model tailored to the implementation of adjuvant radiotherapy in a cohort of 4180 GBC patients. 10wever, it's worth noting that this model lacked the inclusion of surgical margin status and detailed information about the extent of surgical resection, possibly limiting its applicability. 11,12Given this context, the development of more comprehensive and precise nomograms holds promise in enhancing predictive accuracy for GBC patients who have undergone curative-intent resection.
In this study, we formulated a pair of prognostic nomograms tailored to GBC patients who have undergone curative-intent resection, integrating both pre-and postoperative data.The first nomogram serves as a valuable tool for guiding the selection of surgical treatment, while the second nomogram holds the potential for accurately forecasting individual postoperative outcomes.

| Patients and study design
We conducted this study at the Eastern Hepatobiliary Surgery Hospital in Shanghai, enrolling consecutive patients who had undergone curative-intent resection for pathologically confirmed GBC between

| Operative procedures
The surgical approach followed the previously reported strategy. 13dical surgery encompassed en bloc resection of the gallbladder, partial resection into the liver, and dissection of regional lymph nodes.
Partial hepatectomy referred to the removal of a wedge with a 2 cm margin (including segments IVb/V), extended right/left hepatectomy, or right trisectionectomy.Regional lymph nodes included those situated on the hepatoduodenal ligament, hepatic artery, and those located behind the pancreatic head.When adjacent organs (such as the bile duct, stomach, duodenum, colon, omentum, and pancreatic head) were invaded, they were also resected to achieve an R0 resection.In this context, R0 resection indicated pathologically negative transactional margins, R1 resection denoted the presence of microscopically evident residual disease (positive margins), and R2 resection signified the presence of gross (macroscopic) residual disease 14 Lymph metastasis was defined as N1 for one to three positive nodes and N2 for four or more positive nodes, as stipulated in the AJCC staging system (8th edition).

| Follow-up
The established follow-up protocol encompassed regular physical examinations and laboratory assessments, which included monitoring CEA and CA19-9 levels.These evaluations were conducted every 3 months during the initial 2 years and shifted to a 6-month interval for the subsequent 3 years.In cases where CA 19-9 levels were elevated or signs of potential recurrence were observed, enhanced CT, MRI, or PET-CT scans were promptly conducted.Depending on the circumstances at the time of recurrence, interventions such as reoperation, (neo)adjuvant therapy, radiotherapy, or traditional Chinese medicine treatment were employed.

| Statistical analysis
OS was defined as the duration spanning from the surgical procedure to either the patient's demise or the last follow-up.Continuous variables with a normal distribution were subjected to Student's t-test, while the Mann-Whitney U test was employed for non-normally distributed variables.Categorical variables were analyzed using the χ 2 test or Fisher's exact test when suitable.The Kaplan-Meier method was employed to construct survival curves, and the log-rank test was used for their comparison.Multivariate analyses were conducted using Cox proportional analysis with backward stepwise selection based on the Akaike information criterion. 15Nomograms predicting OS were devised according to the outcomes of multivariate analyses.
The predictive nomogram's efficacy was gauged using the concordance index (C-index), while predictions were illustrated through Kaplan-Meier curves for quartiles and calibration plots.Model validation utilized 1000 resampling bootstraps. 16The performance of the nomograms was assessed via decision curve analysis (DCA), a procedure outlined in an accessible online tutorial. 17,18Statistical computations were executed using R 2.13.2 (http://www.r-project.org/).p-Values less than .05were deemed statistically significant.

| Clinicopathological features and postresection OS
A total of 429 consecutive GBC patients who underwent curative intent resection were initially identified.Among them, 61 were excluded due to factors including preoperative adjuvant chemoradiotherapy (n = 13), metastatic disease (n = 3), R2 surgical margins (67.8% vs. 42.6%) was notably higher compared to the external validation cohort from the Guangzhou Centre (Table 1).The performed types of resection in GBC patients are outlined in Supplemental Table 1, and the associated surgical complications are detailed in Supplemental Table 2.
The median OS duration for the training cohort was 22.2 months and for the validation cohort, it was 23.5 months.The 1-, 3-, and 5-year OS rates for the training cohort were 68.5%, 42.0%, and 24.4%, respectively, and for the validation cohort, these rates were 58.1%, 34.2%, and 26.4%, respectively.These calculations were based on data until May 15, 2022.Notably, no significant disparities in the 1-, 3-, and 5-year OS rates were observed between the two cohorts (p = .543).

| Nomogram performance in the training cohort
The preoperative nomogram, which integrates all the identified independent risk factors for OS in the training cohort, is depicted in Figure 1A.The bootstrap-corrected C-index for predicting OS was calculated as 0.661 (95% CI, 0.627 to 0.694).Notably, the calibration plot for the OS probability at 3 and 5 years post-surgery (Figure 2A,B) illustrates an excellent alignment between the nomogram predictions and the actual observed data.Furthermore, the OS nomogram effectively stratified patients into four distinct prognostic subgroups.These subgroups exhibited 5-year OS rates of 48.1%, 19.0%, 15.6%, and 8.1%, respectively ( p < .001,Supplemental Figure 1A).presented in Figure 1B.The bootstrap-corrected C-index for predicting OS was determined as 0.778 (95% CI: 0.756-0.800).The calibration curves, after bootstrap correction, for the nomogram's ability to predict the probability of OS at 3 or 5 years following surgery exhibited favorable fitting (Figure 3A,B).Notably, the subgroups generated by the nomogram showed distinct 5-year OS rates of 57.2%, 25.9%, 7.8%, and 1.0%, respectively ( p < .001,Supplemental Figure 1B).Furthermore, the OS nomogram's C-index surpassed that of the 8th TNM system (0.778 vs. 0.686, p < .001).Moreover, the Decision Curve Analysis (DCA) indicated that the OS nomogram yielded a greater net clinical benefit in predicting 5-year OS in comparison to the 8th TNM system (Supplemental Figure 2).

| External validation of the nomogram
The  An element integrated into the postoperative nomogram but not present in other existing staging systems was the status of the surgical resection margin.Extensive resection is considered imperative for disease eradication.Attaining R0 resection holds significance in determining prolonged survival, with corresponding 5-year survival rates ranging from 36% to 38%. 5,19,20Nonetheless, the efficacy of surgery for advanced GBC remains a subject of debate.Earlier investigations suggested that proactive surgical intervention could enhance survival outcomes for individuals with advanced GBC. [21][22][23] Conversely, some researchers indicated that tumor biology and stage, rather than the extent of resection, played a more pivotal role in long-term survival.Addressing these concerns necessitates further prospective studies.
The postoperative nomogram also encompassed lymph node metastasis as a crucial prognostic determinant. 24Prior research have underscored that positive regional lymph nodes stand as a significant adverse prognostic indicator for GBC post-resection. 5,25Furthermore, the count of positive lymph nodes autonomously governs the notable prognosis for GBC. 26Additionally, the log odds of the number of metastatic lymph nodes and the lymph node ratio have been explored as means to gauge the prognostic impact of lymph node status in GBC patients. 25In this investigation, nodal involvement was categorized into two stages based on the 8th AJCC stage system.In conclusion, considering the elevated incidence of nodal involvement in GBC patients undergoing surgical resection, the execution of regional lymphadenectomies is imperative to achieve R0 resection.
Our study encompassed regional lymph nodes situated on the hepatoduodenal ligament, hepatic artery, and in the vicinity of the pancreatic head.
The postoperative nomogram also integrated tumor location as a contributing factor.Yang et al. have previously highlighted that gallbladder neck tumors, instead of jaundice, which notably curtails the prospects of radical resection, can independently forecast unfavorable outcomes for GBC patients. 13This could potentially be elucidated by the presence of a multitude of organs and structures in the gallbladder neck vicinity, including the contiguous bile duct, portal vein, liver, duodenum, and colon, which may demonstrate early tumor spread, thereby complicating resection and radiotherapy approaches. 27nce, undertaking resection of the extrahepatic bile duct proves valuable for patients afflicted with gallbladder neck tumors.

9 (
January 2008 and December 2018.The data of these patients were collected prospectively.The inclusion criteria consisted of the following: (a) preoperative performance status score of 0-1; (b) absence of distant metastasis; (c) no previous history of other carcinomas; d. no prior anti-tumor therapy before surgery.The exclusion criteria encompassed cases with macroscopically positive (R2) surgical margins, insufficient clinical information, and patients lost to follow-up.All eligible patients undergoing resection at the Shanghai center were included in the training cohort.For external validation, a separate cohort of consecutive patients at the Sun Yat-Sen University Cancer Center in Guangzhou, between February 2007 and December 2018, was established using the same selection criteria.Ethical approval was granted by the Institutional Ethics Committee of the hospital, and all patients provided informed consent for their data to be collected for the study's purposes.Both centers shared similar indications for resection and perioperative management.Preoperative evaluations encompassed liver function tests, routine blood panels, prothrombin time assessments, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-CA19-9) tests.Imaging studies included chest radiography, abdominal ultrasonography, and contrast-enhanced computed tomography (CT)/ magnetic resonance imaging (MRI) of the abdomen.Comprehensive assessments of cardio-pulmonary function were conducted for elderly patients or those with significant co-existing conditions.For some jaundiced patients, percutaneous transhepatic cholangiography drainage (PTCD) or endoscopic retrograde cholangio-pancreatography (ERCP) was typically performed approximately a week before hepatectomy if the re-evaluation of hepatic function was deemed necessary.The clinical staging was determined based on the pathological tumor-node-metastasis (pTNM) classification in accordance with the 8th edition guidelines of the American Joint Committee on Cancer (AJCC).

(n = 23
), history of other malignancies (n = 4), perioperative death (n = 10), and early loss to follow-up after discharge (n = 8).The training cohort was composed of the remaining 378 patients.In the external validation cohort, 22 out of 130 patients were excluded due to preoperative adjuvant chemoradiotherapy (n = 4), R2 surgical margins (n = 10), perioperative death (n = 3), and loss to followup (n = 5).The remaining 108 patients constituted the external validation cohort.The baseline clinicopathological characteristics in the cohorts exhibited general similarity.Yet, within the training cohort, the percentage of GBC patients with preoperative serum CA 19-9 levels >37 The postoperative nomogram, which encompasses all the independent risk factors for OS identified in the training cohort, is T A B L E 1 Baseline characteristics of patients between training cohort and validation cohort.

3
Calibration curves for OS prediction by the post-operative nomogram.(A and B): 3-and 5-year postoperative OS in the training cohort.(C and D): 3-and 5-year postoperative OS in the external validation cohort.The x-axis represents the nomogram prediction; the y axis indicates the actual OS.
Multivariable analysis of OS based on the preoperative data in the training cohort.Multivariable analysis of OS based on the postoperative data in the training cohort.pT category and pN category were defined according to the 8th edition of the AJCC staging system.
Abbreviations: ALT, alanine aminotransferase; CA19-9, cancer antigen 19-9; CEA, carcinoembryonic antigen; GBC, gallbladder carcinoma; IQR, interquartile range; TBIL, total bilirubin.a(I),imagingstudies; (P), postoperative pathological examinations.bpTcategoryand pN category were defined according to the 8th edition of the AJCC staging system.T A B L E 2 a (I), imaging studies.The preoperative nomogram similarly demonstrated its efficacy in predicting OS, displaying C-indices of 0.615 (0.552-0.679) in the validation cohort.It maintained its capacity to accurately categorize patients into distinct prognostic groups within both cohorts (with respective 5-year OS rates of 45.0%, 29.4%, 26.9%, and 5.3% for the four subgroups in the validation cohort; p < .001,SupplementalFigure1C).T A B L E 3 b